1. Field of the Invention
The present invention relates to an intranasal pharmaceutical compositions comprising calcitonin as an active ingredient and specific concentrations of citric acid or a salt thereof as a stabilizer and absorption enhancer.
2. Description of the Related Art
Calcitonins are a class of polypeptide hormones that are used in the treatment of a variety of conditions including osteoporosis, Paget's disease and malignant hypercalcemia. They are composed of amino acids and have been extracted from a number of sources including salmon, porcine, eel and human. Calcitonins with amino acid sequences identical to the natural forms have been produced by chemical synthesis as well as by recombinant technology.
Given their size and chemical composition, calcitonins were originally administered by subcutaneous or intramuscular injection. Other routes of administration were technically difficult because calcitonins were poorly absorbed through tissue and were readily degraded by bodily fluids. Despite these obstacles, a formulation (U.S. Pat. No. 5,759,565) was developed that could be administered via the nasal route. The nasal formulation was designed to be stored in a multi-dose container that was stable for an extended period of time and resisted bacterial contamination. The preservative in the formulation, benzalkonium chloride, was found to enhance the absorption of salmon calcitonin. However, benzalkonium chloride was reported (P. Graf et al., Clin. Exp. Allergy 25:395-400; 1995) to aggravate rhintis rhinitis medicamentosa in healthy volunteers who were given a decongestant nasal spray containing the preservative. It also had an adverse effect on nasal mucosa (H. Hallen et al., Clin. Exp. Allergy 25:401-405; 1995). Berg et al. (Laryngoscope 104:1153-1158; 1994) disclose that respiratory mucosal tissue that was exposed in vitro underwent severe morphological alterations. Benzalkonium chloride also caused significant slowing of the mucocilary transport velocity in the ex vivo frog palate test (P.C. Braga et al., J. Pharm. Pharmacol. 44:938-940; 1992).